Research topic

Summary

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that plays an important role in the regulation of serum low-density lipoprotein (LDL) cholesterol by downregulation of LDL receptor, and as such is considered a novel target in cholesterol lowering therapy. LDL cholesterol (LDL-C) binds to LDL receptors (LDLRs) on the surface of hepatic cell where the complex is internalized and transported to the endosome. LDL-C dissociates from the receptor and is catabolized whereas the LDLR is recycled to the cell surface for continued clearance of serum cholesterol. PCSK9 affects the receptor recycling pathway by binding to the LDLR and causing degradation of the receptor within the endosome/lysosome compartment. Degradation of the LDLR results in decreased clearance of serum cholesterol, and as a result a higher risk of hypercholesterolemia.
Human genetic studies have shown that “gain-of-function” (GOF) mutations in the PCSK9 gene can lead to a form of familial hypercholesterolemia with a higher risk of cardiovascular disease. In contrast, humans with “loss-of-function” (LOF) mutations in the PCSK9 gene have lower serum cholesterol levels and a lower incidence of cardiovascular disease. Thus PCSK9 had a key impact not only on circulating LDL-C level but also on cardiovascular risk and atherosclerotic process.